Osteosarcoma: Our study with newly diagnosed localized and metastatic osteosarcoma (OS), in collaboration with several other centers, was concluded in the past year, and all patients have completed active therapy. Data currently is being analyzed. One aim of this study was to evaluate the value of dynamic MRI imaging (DEMRI) in predicting response to neoadjuvant chemotherapy. We now have data on this technique in approximately 22 patients studied at the NCI and are still following patients to determine the value of this approach. We have performed gene expression profiling analysis on these tumors in collaboration with Dr. Ching Lau at Texas Childrens Hospital and this data was published in CANCER RESEARCH. These findings will require confirmation in prospective studies. There also is a suggestion that development of metastatic disease may be predictable based upon expression profiles of the primary tumor. The high-dose chemotherapy with autologous stem-cell rescue arm of this study did not improve DFS by greater than 50% in poor-risk patients. We plan on opening a multi-institutional study to evaluate an Astra-Zeneca src-kinase inhibitor that has shown activity in preclinical metastatic models. We performed preclinical testing in our osteosarcoma models and demonstrated that the drug inhibits targets of src and also showed that human osteosarcoma tumors express high levels of activated src. The study will randomize patients who present with pulmonary metastases to receive standard resection of pulmonary nodules vs. surgery plus treatment with the kinase inhibitor to determine whether DFS can be prolonged with treatment. The study will be performed through a new sarcoma treatment consortium called SARC. Ewings Sarcoma: Our new salvage therapy for recurrent osteosarcoma and Ewings sarcoma using a combination of sequential gemcitabine/docetaxel based on preliminary in vitro synergy and previous activity of the single agents was tested through the SARC consortium. The osteosarcoma cohort was fully accrued and terminated due to inactivity. Patients with Ewings sarcoma continue to accrue to the study. We have completed accrual of patients with newly diagnosed Ewings sarcoma to evaluate the effectiveness of a long-acting G-CSF. Patients received standard 5-drug chemotherapy and were randomized to receive standard or long-acting G-CSF. Final analysis of this study is ongoing, and we presented a preliminary analysis at ASCO 2007. The COG Ewings biology study AEWS02B1 opened in January 2003, and we continue to receive specimens as a major center participating in this trial. We continue our study using matched related allogeneic transplant for patients with recurrent Ewings sarcoma and rhabdomyosarcoma. We recently opened a study evaluating treatment of MPNST patients, in both the sporadic- and NF-1-associated setting. We will evaluate the objective response rate of alternating Ifos/etoposide with Adria/Ifos in these patients, followed by surgical resection after 4 cycles of therapy. We have entered 2 patients to date, and this study should open for accrual within the next 3 months across the SARC consortium. Finally, after years of studying IGF signaling in these tumors, we will test the efficacy of a humanized monoclonal antibody directed against the IGFI receptor in these tumors. Based on activity seen in adults with Ewings sarcoma in Phase I study of this antibody, we were approached to study Ewings sarcoma and other pediatric tumors. Again working with the SARC consortium, we have written a Phase II study to evaluate the activity of the Hoffman-Roche IGFIR antibody in Ewings sarcoma, osteosarcoma, rhabdomyosarcoma and synovial sarcoma. The protocol is currently undergoing review, and we hope to enter our first patients by late fall 2007. This study will enter patients from age 12 and above. In addition, I worked with Dr. Frank Balis in the PET section of the Pediatric Oncology Branch to develop a pediatric Phase I study evaluating this antibody in younger patients with a variety of tumors including the sarcomas mentioned above, but also tumors that occur in younger children that may be IGF-driven including neuroblastoma and Wilms tumor